1. Field of the Invention
The present invention relates generally to the fields of molecular medicine and drug delivery and, more specifically, to molecules that home to a specific organ or tissue.
2. Background Information
Although the effect of a particular pathology often is manifest throughout the body of the afflicted person, generally, the underlying pathology may affect only a single organ or tissue. It is rare, however, that a drug or other treatment will target only the diseased organ or tissue. More commonly, treatment results in undesirable side effects due, for example, to generalized toxic effects throughout the patient""s body. It would be desirable to selectively target organs or tissues, for example, for treatment of diseases associated with the target organ or tissue. In particular, targeting of an organ or tissue can be useful for directing the expression of a gene to a certain organ or tissue because incorporation of a foreign gene into nontargeted cells can cause unwanted side effects such as malignant transformation.
Most therapeutic substances are delivered to the target organ or tissue through the circulation. The endothelium, which lines the internal surfaces of blood vessels, is the first cell type encountered by a circulating therapeutic substance in the target organ or tissue. These cells provide a target for selectively directing therapies to an organ or tissue.
Endothelium can have distinct morphologies and biochemical markers in different tissues. The blood vessels of the lymphatic system, for example, express various adhesion proteins that serve to guide lymphocyte homing. For example, endothelial cells present in lymph nodes express a cell surface marker that is a ligand for L-selectin and endothelial cells in Peyer""s patch venules express a ligand for the xcex14xcex27 integrin. These ligands are involved in specific lymphocyte homing to their respective lymphoid organs. Thus, linking a drug to L-selectin or to the xcex14xcex27 integrin may provide a means for targeting the drug to diseased lymph nodes or Peyer""s patches, respectively, provided that these molecules do not bind to similar ligands present in a significant number of other organs or tissues.
Although the homing molecules present in the blood vessels of non-lymphoid tissues have not been clearly defined, certain observations of lymphocyte circulation suggest that organ and tissue specific endothelial markers exist. Similarly, the homing or metastasis of particular types of tumor cells to specific organs or tissues further suggests that organ and tissue specific markers may exist. Thus, a need exists to identify molecules that can bind to such organ or tissue specific markers and, therefore, can home to the organ or tissue. The present invention satisfies this need and provides related advantages as well.
The present invention provides molecules that selectively home to various normal organs or tissues, including to lung, skin, pancreas, retina, prostate, ovary, lymph node, adrenal gland, liver or gut. For example, the invention provides lung homing peptides such as those containing a GFE motif, including the peptides CGFECVRQCPERC (SEQ ID NO: 1) and CGFELETC (SEQ ID NO: 2); skin homing peptides such as CVALCREACGEGC (SEQ ID NO: 3); pancreas homing peptides such as the peptide SWCEPGWCR (SEQ ID NO: 4); and retina homing peptides such as those containing an RDV motif, including the peptides CSCFRDVCC (SEQ ID NO: 5) and CRDVVSVIC (SEQ ID NO: 6).
The invention also provides conjugates, comprising an organ or tissue homing molecule linked to a moiety. Such a moiety can be a therapeutic agent such as a toxin, an agent that inhibits cell death, an agent that alters the production or actively of a deleterious or beneficial substance by a cell, or an agent that alters proliferation of a cell exposed to the agent. A moiety also can be a detectable agent such as a radionuclide, or a tag such as a chambered microdevice or an insoluble chromatography support. Such conjugates of the invention are useful for directing the moiety to a selected organ or tissue.
The invention also provides methods of using an organ homing molecule of the invention to diagnose or treat a pathology of the lung, skin, pancreas, retina, prostate, ovary, lymph node, adrenal gland, liver or gut by administering a molecule that homes to the selected organ or tissue to a subject having or suspected of having a pathology. For example, a pathology of lung, skin, pancreas, retina, prostate, ovary, lymph node, adrenal gland, liver or gut can be treated by administering to a subject having the pathology a conjugate comprising an appropriate organ homing molecule linked to a therapeutic agent. Similarly, a method of identifying a selected organ or tissue or diagnosing a pathology in a selected organ by administering to a subject a conjugate comprising an appropriate organ homing molecule linked to a detectable agent.
The invention further provides methods of identifying a target molecule in lung, pancreas, skin, retina, prostate, ovary, lymph node, adrenal gland, liver or gut by detecting selective binding of the target molecule to a lung, skin, pancreas, retina, prostate, ovary, lymph node, adrenal gland, liver or gut homing molecule, respectively. For example, a peptide that selectively homes to lung can be attached to a solid matrix, a sample of lung can be obtained and passed over the affinity matrix under conditions that allow specific binding of the target molecule, and the target molecule can be collected and identified. Thus, the invention also provides a target molecule, which binds an organ homing molecule, particularly a lung, skin, pancreas, retina, prostate, ovary, lymph node, adrenal gland, liver or gut homing molecule. Such a target molecule can be useful, for example, for raising an antibody specific for the target molecule.